Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (20 page)

This paper may seem somewhat unorthodox in a monograph on screening procedures. However, we are eager to present the role of chance in obtaining new leads for chemotherapy and to illustrate this with a specific example. The results of our research, which are presented here in detail for the first time, should not be considered in terms of a new chemotherapeutic agent, but rather in terms of a chance observation that has led to the isolation of a substance with potential chemotherapeutic possibilities.

Clearly, Noble was trumpeting the value of having
stumbled
across a discovery. He claimed that if he and his colleagues had restricted their search to plants with suspected anticancer properties, they would have missed the periwinkle. Big Science is not a sine qua non.

The cancer worker in the smaller institution or the academic department must view with awe the vast chemotherapeutic screening projects in progress in the United States; at the same time, however, he must consider what contribution he is in a position to make. Perhaps the role of chance observation is neglected in his consideration of ways of searching for new agents. Although somewhat irregular in comparison with the systematic prediction, synthesis and screening of an entirely new series of compounds, chance observations may well be worthy of greater consideration than they have received.

Perhaps reflecting the organizer's lack of interest in a paper so titled, Noble's report to the meeting was presented at midnight, but he related this fact good-naturedly: “By this time, in the early morning, the audience, besides the chairman, had been reduced to [my two co-investigators], the janitorial staff, a few scattered listeners, and a small cluster of scientists.”
³
The latter was a group from the Eli Lilly Company who, noting his listing in the program, had previously arranged to meet with Noble to discuss their preliminary data. Gordon Svoboda and his colleagues had followed an almost identical approach after they too had discovered that
Vinca
extracts lacked antidiabetic activity, but in a general screening program at Eli Lilly their activity against a transplanted acute lymphocytic leukemia in the mouse was
revealed.
⁴
A fruitful collaborative effort between Noble's group and the Eli Lilly research staff was undertaken. In 1961 Svoboda reported the isolation of vincristine, an alkaloid with almost identical chemical structure, but with different toxicity and range of clinical applications.

At about this time, the botanical name for the plant was changed to
Catharanthus roseus,
but it remains commonly referred to as
Vinca rosea.
Pure isolation of the alkaloid required gargantuan efforts. For example, fifteen tons of dried periwinkle leaves were required for the production of one ounce of vinblastine. Biological screening was enormously facilitated by the availability of a mouse leukemia, P-1534, that was exquisitely sensitive to the drugs. Other animal tumors were equally responsive, and clinical trials on humans were soon undertaken with rewarding results. At the time, active compounds could move from the laboratory with remarkable speed. Both vinblastine and vincristine gained FDA approval within three years of their discovery.

The periwinkle alkaloids function as poisons at a critical stage of cell division, preventing the cancer cell from reproducing.
⁵
Vincristine used together with steroids is presently the treatment of choice to induce remissions in childhood leukemias. Vinblastine, in a regimen with other agents, has resulted in an astonishing cure rate of over 90 percent in patients with testicular carcinomas. Employed in adult Hodgkin's lymphoma along with other drugs, the
Vinca
alkaloids have raised the five-year survival prospect to 98 percent.

Rather than preparing the compounds synthetically, a long and expensive process, Eli Lilly continues to process the agents from plants, using around eight tons of
C. roseus
annually.
⁶
What started as a false trail in medicinal folklore led to a chance discovery that resulted in triumphs for combination chemotherapy.

12

A Heavy Metal Rocks

The Value of Platinum

How a precious metal was shown to be useful against cancer is a fascinating story of a chance occurrence exploited by an astute researcher. The discovery arose from an unlikely source in an obscure biophysics laboratory and in a surprising way.

In the mid-1960s Barnet Rosenberg, a biophysicist at Michigan State University, was studying the effects of electric currents on
E. coli
bacteria growth. His goal initially was to sterilize medical supplies and to preserve food. He carefully chose the bacterium,
E. coli,
particularly common in the gastrointestinal tract and a frequent contaminant.
E. coli
is easy to grow in the lab and it reproduces very quickly. Furthermore, its chromosome structure was well understood. He devised a simple visual method to evaluate the effects of an electrical current upon bacterial growth by stirring the
E. coli
into a nutrient broth in glass chambers. And he selectively used platinum wire electrodes in the brew because of their presumed chemical inertness—all logical and discrete actions. Actively reproducing in the culture medium, the bacteria turned the brew cloudy. When Rosenberg zapped it with an electrical current, the solution cleared within two hours. The findings were easily reproducible. Zapping repeatedly turned the turbid culture clear.

Growth of
E. coli
in a chamber of culture medium ceased within two hours after the small electrical charges went through it. When
Rosenberg examined the medium under his microscope, he saw that the
E. coli
had ceased dividing, and the bacterial cells were essentially in an arrested stage of growth. Understandably, Rosenberg first attributed this effect to the electric current, but further experiments, often marked by false leads and blind alleys, finally led him to a startling realization.

In the original design of the experiment, Rosenberg had purposely chosen platinum as the material for the electrodes—because of its presumed chemical inertness—and a specific voltage to eliminate electrolysis effects and electrode polarization. In Rosenberg's refreshingly candid words: “both are mistaken ideas which led, via serendipity, to the effects described” and the realization that the inhibition of bacterial reproduction was due, not to the electrical effects, but instead to the unexpected release of platinum ions into the culture solution from the electrodes.
¹
What caused the beneficial effect was the material that he was using to convey the electrical current. Had he chosen an electrode device made of silver or aluminum or chromium, his experiment would have led nowhere.

At this point, Rosenberg could have methodically continued along the original plan for his research. Fortunately, he saw the potential usefulness of his discovery to cancer therapy and reported his findings to the National Cancer Institute. Excited researchers subsequently found various platinum compounds to be very effective agents in many advanced tumors because of an amazing ability platinum has: it blocks cell division.
²

Cisplatin, a platinum salt with the chemical
cis
configuration, proved to be of particularly great clinical value,
³
and it became the foundation for curative regimens for advanced testicular cancer, as exemplified in Lance Armstrong. By the time the then twenty-seven-year-old cyclist sought treatment for one testicle swollen to twice its normal size (“I'm an athlete, I always have little aches and pains,” he told one reporter), the cancer had spread to his lungs and brain. After being cured by cisplatin, Armstrong powered to his seventh Tour de France victory. Cisplatin also works well against ovarian cancer and cancers of the head and neck, bladder, esophagus, and lung. Thus, an
unlikely source of bacteriologic research led to an unexpected discovery of another major category of chemotherapeutic agents.

As Good as Gold

How another precious metal was discovered as a medical treatment is also a fascinating example of serendipity. Injections of gold salts are commonly used today in patients with rheumatoid arthritis, a frequently debilitating disease that attacks the joints, destroying cartilage and inflaming the lining between joints. It affects about 2.1 million people in the United States, usually women between the ages of twenty-five and forty.

The use of gold salts as a treatment to arrest the progress of the disease and to induce remission began with an observation in 1890 by Robert Koch, the father of modern microbiology. He noted that gold salts inhibited the growth of tuberculosis bacilli in test tubes. Early researchers believed tuberculosis initiated rheumatoid arthritis. In the 1920s, based on this mistaken belief, rheumatologists began administering gold injections to their patients with good results. It became clear later that this had nothing to do with tuberculosis, but rather that gold therapy acts by slowing disease progression and damage to joints. Exactly how gold does this is still not well understood.

13

Sex Hormones

Some people collect stamps, others coins, others fine art. Charles Huggins, a professor of surgery at the University of Chicago School of Medicine, collected prostatic fluid from dogs. His interest was in the biochemistry of seminal fluid. Secretions of the prostate gland form much of the ejaculatory fluid. The research was at times frustrated by the formation of prostate tumors in some of the dogs. Dogs are the only species besides humans known to develop cancer of the prostate—an incidental fact that turned out to be fortuitous.

After castrating a few dogs to see what effect testosterone injections might have on production of prostate fluid, he noticed something totally unexpected. Some tumors regressed, specifically those in elderly dogs whose tumors had arisen spontaneously (in other words, tumors that had come about on their own as opposed to being introduced into the dog by an experimenter). Huggins wondered, could it be that these tumors were hormone-dependent? As castration would obviously not have been a treatment option for humans, he injected estrogen into the dogs to produce, in effect, chemical castration. This, too, caused the tumors to regress. He had stumbled over a new threshold. This “Eureka!” moment led to the realization that some tumors are, in fact, hormone-dependent. Professor Huggins reported his results in the
Journal of Experimental Medicine
in 1940.
¹

He then began experimenting with injecting estrogen into men with prostate cancer that had spread to their bones. To his delight, the
tumors regressed and the bone pain was relieved. A synthetic estrogen, stilbestrol, was as effective as naturally occurring estrogens. By 1950, in a cooperative study involving many surgeons, some 1,800 successful cases had been reported, leaving little doubt that a treatment had been found that at least delayed the progress of an otherwise intractable cancer. A breakthrough had been achieved. The discovery that estrogen therapy can control the growth and spread of prostate cancers provided the first clinical evidence that some human tumors respond to their hormonal environment. And for the first time, a synthetic drug was shown to work against cancer. Huggins, who had not been originally working on cancer, was awarded the Nobel Prize in 1966 for this valuable finding that saved many lives.

Prostate cancer is the second most common form of cancer. (In 2003, about 220,000 cases were diagnosed in the United States, and almost 29,000 men died of the disease, according to the American Cancer Society.) Huggins's breakthrough showed that some cancers are dependent on sex hormones. A turning point had been reached. A product of the human body itself rather than toxic or radioactive agents could be exploited as a cancer cure.

Tamoxifen for Breast Cancer

A powerful cancer drug, tamoxifen, arose unexpectedly from infertility research. In the late 1960s a synthetic compound was used in some countries to treat infertility in women because of its estrogenlike activity, which stimulated ovulation.
²
Research then came across an analog, tamoxifen, with an unanticipated value: it acted as an antiestrogen by virtue of its ability to block estrogen receptors. Tamoxifen came to be widely used in the treatment of breast cancer. It helps only women with estrogen-dependent breast cancer, which accounts for about 60 percent of breast cancers.
³

14

Angiogenesis

The Birth of Blood Vessels

In August 1945 a report was published in the
Journal of the National Cancer Institute
that seemed to have little import at the time. Two researchers had noticed that tumor cells somehow elicit the growth of new blood vessels from their host. Furthermore, they speculated that a “specific substance” is produced by the tumor cells.
¹
Their report aroused virtually no interest. The circulatory system was not viewed as a fertile field for research, and intense focus on cancer research did not develop for another two decades. The report was a striking example of prematurity in discovery.

Nearly twenty years later, in the early 1960s, a twenty-eight-year-old rabbi's son and Harvard Medical School graduate named Judah Folkman unexpectedly and indeed accidentally came up with a novel strategy to combat cancer. He was working at the National Naval Medical Center in Bethesda, Maryland, investigating potential substitutes for blood in transfusions for use in hospitals on aircraft carriers, when he made a momentous observation.